Field of the Invention
The invention relates to the field of field effect transistors used as solid-state biosensors. More particularly, the invention is directed to a field effect transistor and arrays using the same in which the gate is acting as an “open base” with a fixed parallel plate of carbon nanotubes, which has been functionalized and which exhibits characteristics of ballistic transport (quantum tunneling) between the analyte and the antibody due to the hybridization process. G06F 11/00
Prior Art
“Method and Apparatus for Forming a Homeostatic Loop Employing an Aptamer Biosensor”, U.S. Pat. No. 8,145,434, issued Mar. 27, 2012, hereby incorporated by reference in its entirety. Controlling the covalent bonding of antibodies onto functionalized carbon nanotubes using a single field effect transistor is a key step in the design and preparation of nanotube-based transducer for targeting cancer cells, biomarkers and synthetic oligonucleic acid or peptide. The chemical biosensors forming the bioFET architecture (cellular arrays) undergo electrical impedance (capacitive) changes due to hybridization of biomarkers which are realized on a scale of pico-amp increments.
Over the last decade, a variety of protein and DNA sensors have been developed circumventing the need for fluorescent labeling and optical imaging. Development of these label-free detection schemes is motivated by the need for faster, lower-cost detection of biomolecular agents. This access to quantitative information about the presence of specific bio-molecules in a patient's body or a pathogen in food or water is a critical step toward more accurate and personalized medical care as well as early detection of epidemiologic trends. To detect unlabeled bio-molecules, the label-free detection schemes utilize intrinsic protein properties such as polarizability, mass and electric charge, where a bioFET cell's reliance on the dielectric constant of bio-molecules changes the FET's gate characteristics and thus enable quantification of the hybridization process.
In the class of charge-sensitive biosensors, the use of semiconducting carbon nanotubes is extremely promising due to the electrical as well as the spatial properties of carbon nanotubes, as a mechanical scaffolding in support of the chemical linker and its antibody payloads, as well as the ballistic transfer characteristics of their hollow cylinders with their sp2 bonding, which improve the device's characteristics.
Whereas a conventional field-effect transistor (FET) uses a gate contact to control the conductance of the semiconductor between its sources and drain contacts, the BioFET sensor array replaces the gate structure response, by the formation of a biofunctionalized layer of immobilized probes formed out of carbon nanotubes which act as surface receptors to attenuate the gate. When, a matching target molecule binds to the receptor, the charge distribution in the boundary layer at the liquid-transducer interface of the device changes. Hence this modulation of the conductance of the transducer by the selective specificity of the analyte binding to the antibody (the hybridization), results in an electrical detection of Vds verses Ids, (Gv) by the bioFET gate structure, thereby improving the receptivity, gain, accuracy and repeatability of measurement by the device.
One of the drawbacks of the current state of the art is the inability of existing techniques to form an integrated apparatus that creates real time mimicry of the cellular biological processes of hybridization by the “sensor molecule”, namely the molecule that selectively binds with a molecule whose concentration is to be measured in a sample. An example for such a sensor molecule may be an antibody, an antigen, a protein, a receptor, an aptamer, a peptide, a DNA strand, or an enzyme.
Biosensors which continuously monitor their surroundings to provide background statistics and warnings against unhealthy conditions are well known in the art of biosensors. There are numerous examples of gravimetric biosensors. The basis of detection is the decrease in the resonant frequency of a resonator that occurs as analyte species attaches to the resonating element. Analyte specificity is conferred for biological analytes by functionalizing the exposed surface of the gate and its conductance and its electrical resolution to enable a measurement that phenomenologically mimics the underlying biology.
For example Arwin, et al. U.S. Pat. No. 4,072,576 teaches a method for studying biochemical reactions in which a substance, whose activity or concentration is to be determined and where the affects a substrate specific for a biochemical reaction is measured. In many of the prior art applications the electrodes are coated with the substrate, determining a control value. The capacitance in a measuring device containing the electrodes is determined, the target substance is introduced into the measuring device, and the change in capacitance is measured, thereby obtaining a quantitative measure of the activity or concentration of the substance present in the sample affecting the specific substrate on the electrodes.
Conventional biosensors suffer from their inability to distinguish between like molecules and their timing of hybridization during the measurement process. In another class of biosensors the molecular interactions can be detected electronically through the polarizability of biological molecules' affinity, or optically through the use of fluorescence tags, radiometrically through the use of radioactive labeled tags, or acoustically. The use of labeling molecules is time consuming and requires many preparatory steps, which make the technique impractical in a disposable label free application.
Many variations on the theme of galvanometric and optically coupled biosensors where developed and their bases fundamentally follow the application of by Bergveld (1970) where the principle of the so-called “Ion Selective Field Effect Transistor”, (ISFET) is the common thread. An example of such use is Schenck, U.S. Pat. No. 4,238,757 which describes a field effect transistor including a conventional source and drain electrodes which employs, in the gate region, a layer of an antibody specific to a particular antigen.
Rice U.S. Pat. No. 4,314,821 describes a method and kit for determining the total amount of an immunologically-reactive substance in a liquid sample containing interfering material capable of binding to an antigen. The method involves the steps of: contacting a liquid sample containing an antibody with the surface of a piezoelectric oscillator having a layer of antigen specific for the antibody attached thereto; washing and drying the oscillator; and measuring the resonance frequency of the oscillator.
Malmros, U.S. Pat. No. 4,444,892 introduces a sensor and semiconductor device for determining the concentration of an analyte in a medium. The device features an element constructed of semiconductive organic polymer associated with a binding substance having a specific affinity for the analyte.
Lida, et al. U.S. Pat. No. 4,900,423 discloses an enzyme sensor comprising an enzyme acting specifically on a substrate and a transducer for converting into an electrical signal the quantitative change of a substance or heat, which is produced or consumed during an enzyme reaction.
In another class of biosensor designed for optical surface plasmon resonance (SPR) detection of binding of a ligand-binding agent to the surface-bound ligand, the biosensor surface is a transparent dielectric substrate coated with a thin metal layer on which the monolayer is formed, where the substrate and metal layer form a plasmon resonance interface. The detector functions to excite surface plasmons, at a plasmon resonance angle that is dependent on the optical properties of the metal film and attached monolayer, and to detect the shift in plasmon resonance angle produced by binding of ligand binding agent to the ligand. As in the previous classes of available biosensor, the SPR apparatus is limited to laboratory setting with highly qualified individual to operate and assess the results obtained from the measurement. The use of biosensor designed for optical detection of binding of a ligand-binding agent to the surface bound ligand, and where the detector functions to irradiate the biosensor surface with a light beam, and detect a change in the optical properties of the surface layer, e.g., monolayer with embedded heterodimer, produced by binding of ligand binding agent to the ligand, suffer from the same limitations outlined above.
The problem which has not been solved by the prior art is how to reliably measure the degree and time sequencing of a plurality of biomarkers in a fluid in real time in such a way that the degree and time sequencing of the plurality of biomarkers in a live cell is mimicked and resolved.